PRMT5 inhibition has a potent anti-tumor activity against adenoid cystic carcinoma of salivary glands
Abstract Background Adenoid cystic carcinoma (ACC) is a rare glandular malignancy, commonly originating in salivary glands of the head and neck. Given its protracted growth, ACC is usually diagnosed in advanced stage. Treatment of ACC is limited to surgery and/or adjuvant radiotherapy, which often f...
Saved in:
| Main Authors: | , , , , , , , , , , , , , , , , , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
BMC
2025-01-01
|
| Series: | Journal of Experimental & Clinical Cancer Research |
| Subjects: | |
| Online Access: | https://doi.org/10.1186/s13046-024-03270-x |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| _version_ | 1841544197405933568 |
|---|---|
| author | Vasudha Mishra Alka Singh Michael Korzinkin Xiangying Cheng Claudia Wing Viktoria Sarkisova Ashwin L. Koppayi Alexandra Pogorelskaya Oksana Glushchenko Manu Sundaresan Venkat Thodima Jack Carter Koichi Ito Peggy Scherle Anna Trzcinska Ivan Ozerov Everett E. Vokes Grayson Cole Frank W. Pun Le Shen Yuxuan Miao Alexander T. Pearson Mark W. Lingen Bruce Ruggeri Ari J. Rosenberg Alex Zhavoronkov Nishant Agrawal Evgeny Izumchenko |
| author_facet | Vasudha Mishra Alka Singh Michael Korzinkin Xiangying Cheng Claudia Wing Viktoria Sarkisova Ashwin L. Koppayi Alexandra Pogorelskaya Oksana Glushchenko Manu Sundaresan Venkat Thodima Jack Carter Koichi Ito Peggy Scherle Anna Trzcinska Ivan Ozerov Everett E. Vokes Grayson Cole Frank W. Pun Le Shen Yuxuan Miao Alexander T. Pearson Mark W. Lingen Bruce Ruggeri Ari J. Rosenberg Alex Zhavoronkov Nishant Agrawal Evgeny Izumchenko |
| author_sort | Vasudha Mishra |
| collection | DOAJ |
| description | Abstract Background Adenoid cystic carcinoma (ACC) is a rare glandular malignancy, commonly originating in salivary glands of the head and neck. Given its protracted growth, ACC is usually diagnosed in advanced stage. Treatment of ACC is limited to surgery and/or adjuvant radiotherapy, which often fails to prevent disease recurrence, and no FDA-approved targeted therapies are currently available. As such, identification of new therapeutic targets specific to ACC is crucial for improved patients’ outcomes. Methods After thoroughly evaluating the gene expression and signaling patterns characterizing ACC, we applied PandaOmics (an AI-driven software platform for novel therapeutic target discovery) on the unique transcriptomic dataset of 87 primary ACCs. Identifying protein arginine methyl transferase 5 (PRMT5) as a putative candidate with the top-scored druggability, we next determined the applicability of PRMT5 inhibitors (PRT543 and PRT811) using ACC cell lines, organoids, and patient derived xenograft (PDX) models. Molecular changes associated with response to PRMT5 inhibition and anti-proliferative effect of the combination therapy with lenvatinib was then analyzed. Results Using a comprehensive AI-powered engine for target identification, PRMT5 was predicted among potential therapeutic target candidates for ACC. Here we show that monotherapy with selective PRMT5 inhibitors induced a potent anti-tumor activity across several cellular and animal models of ACC, which was paralleled by downregulation of genes associated with ACC tumorigenesis, including MYB and MYC (the recognized drivers of ACC progression). Furthermore, as a subset of genes targeted by lenvatinib is upregulated in ACC, we demonstrate that addition of lenvatinib enhanced the growth inhibitory effect of PRMT5 blockade in vitro, suggesting a potential clinical benefit for patients expressing lenvatinib favorable molecular profile. Conclusion Taken together, our study underscores the role of PRMT5 in ACC oncogenesis and provides a strong rationale for the clinical development of PRMT5 inhibitors as a targeted monotherapy or combination therapy for treatment of patients with this rare disease, based on the analysis of their underlying molecular profile. |
| format | Article |
| id | doaj-art-6623e6a41495406d97c09fcb53096de9 |
| institution | Kabale University |
| issn | 1756-9966 |
| language | English |
| publishDate | 2025-01-01 |
| publisher | BMC |
| record_format | Article |
| series | Journal of Experimental & Clinical Cancer Research |
| spelling | doaj-art-6623e6a41495406d97c09fcb53096de92025-01-12T12:44:40ZengBMCJournal of Experimental & Clinical Cancer Research1756-99662025-01-0144112010.1186/s13046-024-03270-xPRMT5 inhibition has a potent anti-tumor activity against adenoid cystic carcinoma of salivary glandsVasudha Mishra0Alka Singh1Michael Korzinkin2Xiangying Cheng3Claudia Wing4Viktoria Sarkisova5Ashwin L. Koppayi6Alexandra Pogorelskaya7Oksana Glushchenko8Manu Sundaresan9Venkat Thodima10Jack Carter11Koichi Ito12Peggy Scherle13Anna Trzcinska14Ivan Ozerov15Everett E. Vokes16Grayson Cole17Frank W. Pun18Le Shen19Yuxuan Miao20Alexander T. Pearson21Mark W. Lingen22Bruce Ruggeri23Ari J. Rosenberg24Alex Zhavoronkov25Nishant Agrawal26Evgeny Izumchenko27Department of Medicine, Section of Hematology and Oncology, University of ChicagoDepartment of Medicine, Section of Hematology and Oncology, University of ChicagoInsilico MedicineDepartment of Medicine, Section of Hematology and Oncology, University of ChicagoDepartment of Medicine, Section of Hematology and Oncology, University of ChicagoInsilico MedicineDepartment of Medicine, Section of Hematology and Oncology, Northwestern UniversityInsilico MedicineInsilico MedicineDepartment of Medicine, Section of Hematology and Oncology, University of ChicagoPrelude TherapeuticsPrelude TherapeuticsPrelude TherapeuticsPrelude TherapeuticsDepartment of Pathology, University of ChicagoInsilico MedicineDepartment of Medicine, Section of Hematology and Oncology, University of ChicagoDepartment of Pathology, University of ChicagoInsilico MedicineDepartment of Surgery, University of ChicagoBen May Department for Cancer Research, University of ChicagoDepartment of Medicine, Section of Hematology and Oncology, University of ChicagoDepartment of Pathology, University of ChicagoPrelude TherapeuticsDepartment of Medicine, Section of Hematology and Oncology, University of ChicagoInsilico MedicineDepartment of Surgery, University of ChicagoDepartment of Medicine, Section of Hematology and Oncology, University of ChicagoAbstract Background Adenoid cystic carcinoma (ACC) is a rare glandular malignancy, commonly originating in salivary glands of the head and neck. Given its protracted growth, ACC is usually diagnosed in advanced stage. Treatment of ACC is limited to surgery and/or adjuvant radiotherapy, which often fails to prevent disease recurrence, and no FDA-approved targeted therapies are currently available. As such, identification of new therapeutic targets specific to ACC is crucial for improved patients’ outcomes. Methods After thoroughly evaluating the gene expression and signaling patterns characterizing ACC, we applied PandaOmics (an AI-driven software platform for novel therapeutic target discovery) on the unique transcriptomic dataset of 87 primary ACCs. Identifying protein arginine methyl transferase 5 (PRMT5) as a putative candidate with the top-scored druggability, we next determined the applicability of PRMT5 inhibitors (PRT543 and PRT811) using ACC cell lines, organoids, and patient derived xenograft (PDX) models. Molecular changes associated with response to PRMT5 inhibition and anti-proliferative effect of the combination therapy with lenvatinib was then analyzed. Results Using a comprehensive AI-powered engine for target identification, PRMT5 was predicted among potential therapeutic target candidates for ACC. Here we show that monotherapy with selective PRMT5 inhibitors induced a potent anti-tumor activity across several cellular and animal models of ACC, which was paralleled by downregulation of genes associated with ACC tumorigenesis, including MYB and MYC (the recognized drivers of ACC progression). Furthermore, as a subset of genes targeted by lenvatinib is upregulated in ACC, we demonstrate that addition of lenvatinib enhanced the growth inhibitory effect of PRMT5 blockade in vitro, suggesting a potential clinical benefit for patients expressing lenvatinib favorable molecular profile. Conclusion Taken together, our study underscores the role of PRMT5 in ACC oncogenesis and provides a strong rationale for the clinical development of PRMT5 inhibitors as a targeted monotherapy or combination therapy for treatment of patients with this rare disease, based on the analysis of their underlying molecular profile.https://doi.org/10.1186/s13046-024-03270-xAdenoid cystic carcinoma (ACC)Protein arginine methyl transferase 5 (PRMT5)Organoid modelsPatient derived xenografts (PDXs)PandaOmicsWhole exome sequencing |
| spellingShingle | Vasudha Mishra Alka Singh Michael Korzinkin Xiangying Cheng Claudia Wing Viktoria Sarkisova Ashwin L. Koppayi Alexandra Pogorelskaya Oksana Glushchenko Manu Sundaresan Venkat Thodima Jack Carter Koichi Ito Peggy Scherle Anna Trzcinska Ivan Ozerov Everett E. Vokes Grayson Cole Frank W. Pun Le Shen Yuxuan Miao Alexander T. Pearson Mark W. Lingen Bruce Ruggeri Ari J. Rosenberg Alex Zhavoronkov Nishant Agrawal Evgeny Izumchenko PRMT5 inhibition has a potent anti-tumor activity against adenoid cystic carcinoma of salivary glands Journal of Experimental & Clinical Cancer Research Adenoid cystic carcinoma (ACC) Protein arginine methyl transferase 5 (PRMT5) Organoid models Patient derived xenografts (PDXs) PandaOmics Whole exome sequencing |
| title | PRMT5 inhibition has a potent anti-tumor activity against adenoid cystic carcinoma of salivary glands |
| title_full | PRMT5 inhibition has a potent anti-tumor activity against adenoid cystic carcinoma of salivary glands |
| title_fullStr | PRMT5 inhibition has a potent anti-tumor activity against adenoid cystic carcinoma of salivary glands |
| title_full_unstemmed | PRMT5 inhibition has a potent anti-tumor activity against adenoid cystic carcinoma of salivary glands |
| title_short | PRMT5 inhibition has a potent anti-tumor activity against adenoid cystic carcinoma of salivary glands |
| title_sort | prmt5 inhibition has a potent anti tumor activity against adenoid cystic carcinoma of salivary glands |
| topic | Adenoid cystic carcinoma (ACC) Protein arginine methyl transferase 5 (PRMT5) Organoid models Patient derived xenografts (PDXs) PandaOmics Whole exome sequencing |
| url | https://doi.org/10.1186/s13046-024-03270-x |
| work_keys_str_mv | AT vasudhamishra prmt5inhibitionhasapotentantitumoractivityagainstadenoidcysticcarcinomaofsalivaryglands AT alkasingh prmt5inhibitionhasapotentantitumoractivityagainstadenoidcysticcarcinomaofsalivaryglands AT michaelkorzinkin prmt5inhibitionhasapotentantitumoractivityagainstadenoidcysticcarcinomaofsalivaryglands AT xiangyingcheng prmt5inhibitionhasapotentantitumoractivityagainstadenoidcysticcarcinomaofsalivaryglands AT claudiawing prmt5inhibitionhasapotentantitumoractivityagainstadenoidcysticcarcinomaofsalivaryglands AT viktoriasarkisova prmt5inhibitionhasapotentantitumoractivityagainstadenoidcysticcarcinomaofsalivaryglands AT ashwinlkoppayi prmt5inhibitionhasapotentantitumoractivityagainstadenoidcysticcarcinomaofsalivaryglands AT alexandrapogorelskaya prmt5inhibitionhasapotentantitumoractivityagainstadenoidcysticcarcinomaofsalivaryglands AT oksanaglushchenko prmt5inhibitionhasapotentantitumoractivityagainstadenoidcysticcarcinomaofsalivaryglands AT manusundaresan prmt5inhibitionhasapotentantitumoractivityagainstadenoidcysticcarcinomaofsalivaryglands AT venkatthodima prmt5inhibitionhasapotentantitumoractivityagainstadenoidcysticcarcinomaofsalivaryglands AT jackcarter prmt5inhibitionhasapotentantitumoractivityagainstadenoidcysticcarcinomaofsalivaryglands AT koichiito prmt5inhibitionhasapotentantitumoractivityagainstadenoidcysticcarcinomaofsalivaryglands AT peggyscherle prmt5inhibitionhasapotentantitumoractivityagainstadenoidcysticcarcinomaofsalivaryglands AT annatrzcinska prmt5inhibitionhasapotentantitumoractivityagainstadenoidcysticcarcinomaofsalivaryglands AT ivanozerov prmt5inhibitionhasapotentantitumoractivityagainstadenoidcysticcarcinomaofsalivaryglands AT everettevokes prmt5inhibitionhasapotentantitumoractivityagainstadenoidcysticcarcinomaofsalivaryglands AT graysoncole prmt5inhibitionhasapotentantitumoractivityagainstadenoidcysticcarcinomaofsalivaryglands AT frankwpun prmt5inhibitionhasapotentantitumoractivityagainstadenoidcysticcarcinomaofsalivaryglands AT leshen prmt5inhibitionhasapotentantitumoractivityagainstadenoidcysticcarcinomaofsalivaryglands AT yuxuanmiao prmt5inhibitionhasapotentantitumoractivityagainstadenoidcysticcarcinomaofsalivaryglands AT alexandertpearson prmt5inhibitionhasapotentantitumoractivityagainstadenoidcysticcarcinomaofsalivaryglands AT markwlingen prmt5inhibitionhasapotentantitumoractivityagainstadenoidcysticcarcinomaofsalivaryglands AT bruceruggeri prmt5inhibitionhasapotentantitumoractivityagainstadenoidcysticcarcinomaofsalivaryglands AT arijrosenberg prmt5inhibitionhasapotentantitumoractivityagainstadenoidcysticcarcinomaofsalivaryglands AT alexzhavoronkov prmt5inhibitionhasapotentantitumoractivityagainstadenoidcysticcarcinomaofsalivaryglands AT nishantagrawal prmt5inhibitionhasapotentantitumoractivityagainstadenoidcysticcarcinomaofsalivaryglands AT evgenyizumchenko prmt5inhibitionhasapotentantitumoractivityagainstadenoidcysticcarcinomaofsalivaryglands |